Download Natriuretic Peptides in the Regulation of Cardiovascular Physiology

CONTEMPORARY REVIEW
Natriuretic Peptides in the Regulation of Cardiovascular Physiology
and Metabolic Events
Risto Kerkel€a, MD, PhD; Johanna Ulvila, PhD; Johanna Magga, PhD
A
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trial natriuretic peptide (ANP), B-type natriuretic peptide
(BNP), and C-type natriuretic peptide (CNP) are the
known members of the mammalian natriuretic peptide
system. The discovery of natriuretic peptides (NPs) dates
back to 1981, when de Bold et al. found that administration
of atrial extracts into intact rats causes diuresis and
natriuresis.1 In 1983–1984, ANP was then isolated and
purified, and the amino acid sequence was determined in rats
and humans. Whereas atrial ANP levels are higher than those
in ventricles, the ventricular myocardium becomes a major
source for circulating ANP in failing hearts owing to larger
mass.2 In 1988, a homologous peptide with similar biological
activities was isolated from porcine brain and named BNP.3
BNP is expressed in both adult atria and ventricles, but is
mainly released from the ventricles.
The key stimulant for release of ANP and BNP from the
heart is myocardial stretch, whereas the third family member,
CNP, is mainly released from endothelial cells in response to
various cytokines2 as depicted in Figure 1. Classically, ANP
and BNP exert diuretic, natriuretic, and hypotensive actions,
and genetic variations of the NPPA-NPPB locus that increase
the circulating levels of ANP and BNP in patients have been
shown to offer protection from hypertension.4 In the clinical
setting, analysis of serum levels of ANP and BNP is used for
diagnosis of heart failure (HF) and it has also been suggested
that analysis for circulating levels of ANP and BNP may be
useful in monitoring the efficacy of therapies in treatment of
patients with HF. Notably, though, treatment of patients with
b-blockers, which reduces cardiovascular morbidity and
mortality especially in post-MI (myocardial infarction)
From the Department of Pharmacology and Toxicology, Research Unit of
Biomedicine, University of Oulu, Finland (R.K., J.U., J.M.); Medical Research
Center Oulu, Oulu University Hospital and University of Oulu, Finland (R.K.).
Correspondence to: Risto Kerkel€a, MD, PhD, Department of Pharmacology
and Toxicology, Research Unit of Biomedicine, University of Oulu,
P.O. Box 5000, FIN-90014 Oulu, Finland. E-mail: risto.kerkela@oulu.fi
J Am Heart Assoc. 2015;4:e002423 doi: 10.1161/JAHA.115.002423.
ª 2015 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley Blackwell. This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
DOI: 10.1161/JAHA.115.002423
patients, is associated with elevated circulating levels of
ANP and BNP.5 Recombinant human ANP and BNP have been
approved for treatment of acutely decompensated congestive
HF in Japan and the United States, respectively. In addition to
renal effects, during the last decade it has become evident
that NPs have direct effects in multiple other tissues and are
involved in regulation of a variety of biological processes, such
as cardiac hypertrophy, fibrosis, metabolism, angiogenesis,
and cardiomyocyte viability. In this review, we summarize the
recent findings of the cardiovascular effects of NPs with
emphasis on effects of NP signaling on cardiac structure and
function.
Natriuretic Peptides and Their Receptors
All NPs are initially synthesized as preprohormones and their
subsequental cleavage results in formation of biologically
active 28-amino-acid ANP, 32-amino-acid BNP, and 22- and
53-amino-acid CNP.6 ANP is secreted from cardiomyocytes as
active hormone, whereas BNP is secreted from cardiomyocytes as a 108-amino-acid prohormone (proBNP). In circulation, glycosylated proBNP is gradually deglycosylated and
further processed by the proNP convertases, corin or furin, to
inactive NT-proBNP1-76 and active BNP1-32.7 Evolutionary
studies suggest that CNP, which, differently from ANP and
BNP, does not stimulate natriuresis, is the most ancient family
member.
The NPs exert their actions through interaction with their
cell surface receptors. To date, 3 NP receptors (NPRs) have
been identified, and they can be divided into 2 major classes:
guanylyl cyclase-coupled receptors A and B (GC-A and GC-B,
or NPRA and NPRB) and a natriuretic peptide clearance
receptor (NPRC).6 NPRA and NPRB both exist as homodimers
and the intracellular domain consists of a kinase homology
domain, a dimerization domain, and a C-terminal catalytic
domain. Activation of NPRA and NPRB induce elevation of
intracellular cyclic guanosine monophosphate (cGMP) and
activation of its key effector molecule, protein kinase G (PKG),
which is largely thought to exert the cardioprotective effects
of NPs.8 NPRC, on the other hand, lacks the intracellular
guanylate cyclase domain and has been shown to signal to
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Figure 1. NPs are secreted from different cell types or tissue sites and signal through guanylyl cyclase or
G-protein-coupled receptor in various target cells throughout the body. ACM indicates atrial cardiomyocytes; Ang II, angiotensin II; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; cGMP, cyclic
guanosine monophosphate; CM, cardiomyocyte; CNP, C-type natriuretic peptide; EC, endothelial cell; ET-1,
endothelin-1; FB, fibroblast; GI, gastrointestinal; Gi, inhibitory G protein; NPR, natriuretic peptide receptor;
NT-Pro, N-terminal propeptide; PKG, protein kinase G; SMC, smooth muscle cell; VCM, ventricular
cardiomyocytes; VSMC, vascular smooth muscle cell.
inhibitory guanine nucleotide-binding protein (inhibitory G
protein).9 Soluble guanylyl cyclase, on the other hand, is
activated by nitric oxide and was recently shown to mediate
the protective effects of b3-adrenergic receptor activation on
left ventricle (LV) remodeling.10,11 NP activation, secretion,
and signaling in different cell types are summarized in
Figure 1.
Juxtamembrane portions of NPRA and NPRB contain
multiple phosphorylation sites, and phosphorylation of those
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sites has been shown to regulate receptor sensitivity. ANP
and BNP primarily bind and signal through NPRA, whereas
CNP binds to NPRB, and the clearance receptor, NPRC, binds
all NPs.6,12 In the myocardium, all three NP receptors have
been shown to be expressed in both cardiomyocytes and
cardiac fibroblasts.13 NPRA stimulation by ANP or BNP has
been shown to induce an increase in cGMP levels in
cardiomyocytes, whereas NPRB stimulation by CNP was
without effect.13 In cardiac fibroblasts, both ANP and CNP
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hypertrophy.16 The same genetic ANP variant also showed
protection against metabolic syndrome. These findings indicate that NPs may exert multiple cardioprotective effects,
mediated by NP receptors expressed in myocardium, vasculature, and in a variety of other tissues, as indicated in
Figure 2.
Regulation of ANP and BNP Gene Expression
In addition to mechanical stretch, multiple other stimuli, such
as angiotensin II (Ang II), endothelin-1 (ET-1), as well as
adrenergic agonists isoproterenol and phenylephrine induce
ANP and BNP transcription and secretion from cardiomyocytes. Mitogen-activated protein kinases (MAPKs) and,
especially, extracellular signal-regulated kinase (ERK), which
is activated by virtually all hypertrophic stimuli in cardiomyocytes, represent the central pathway regulating transcription
of ANP and BNP.17 Constitutive activation of MEK1 (upstream
activator of ERK) in myocytes induces cardiac hypertrophy
and NP expression,18 but loss of ERK from cardiomyocytes is
Figure 2. NPs regulate key functions of the cardiovascular system. NPs also exert various functions on metabolic events, including enhanced
energy metabolism, favorable body fat profile, and increased insulin sensitivity, the factors closely associated with development of
cardiovascular diseases. BAT indicates brown adipose tissue; NP, natriuretic peptide; RAA, renin-angiotensin-aldosterone system; WAT, white
adipose tissue.
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stimulation induced an elevation in cGMP levels, thus
suggesting that both NPRA and NPRB are functional.13 This
indicates some discrepancy in NP signaling between cardiomyocytes and fibroblasts in the heart.
Numerous studies have demonstrated the central role for
NPs in regulation of blood pressure. Genetic studies in
humans have suggested a role for NPs regulating cardiac
hypertrophy and fibrosis, thus increasing interest in investigating NPs as targets for HF therapy. A study conducted in
Italy showed that carriers of allele 664C>G in ANP promoter,
which results in lower levels of circulating ANP, had increased
LV mass index and increased LV wall thickness.14 In another
study, deletion of 5’-flanking region of the human NPRA gene
found in Japanese patients, which reduced the transcriptional
activity of the gene by 30%, appeared to increase susceptibility to hypertension and LV hypertrophy.15 A study conducted on a cohort of a nondiabetic Swedish population
showed that subjects with the minor allele of rs5068 at the
NPPA-NPPB locus, which results in higher circulating levels of
ANP and BNP,4 was associated with reduced incidence of LV
Myocardial Effects of Natriuretic Peptides
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deficiency have proved fruitful. Cardiac remodeling has been
investigated in mice lacking the Npr1 gene (encoding for
NPRA), which effectively blunts the effects of ANP and BNP. In
vitro and in vivo studies concerning cardiovascular effects of
natriuretic peptides are represented in Table 1. These data
categorically demonstrate that NPRA signaling is an intrinsic
signaling mechanism in the myocardium that inhibits both
cardiac hypertrophy and fibrosis. Notably, ANP and BNP
appear to inhibit cardiac fibrosis by modulating reninangiotensin-aldosterone (RAA) system signaling.
Apart from reducing hypertrophy and fibrosis, NPRA
activation may also benefit cardiac function in HF, as
demonstrated in animal models of HF (Table 1). In humans,
treatment of HF patients with recombinant BNP was shown to
cause a dose-related decrease in pulmonary-capillary wedge
pressure.39
The NP/NPRA system also acts as regulator of angiogenesis in the heart and skeletal muscle. Thus, in addition to
reducing blood pressure, cardiac hypertrophy, and fibrosis,
NPs may also signal to enhance angiogenesis and help
neovascularization in injured muscle. It remains to be
investigated whether enhanced NPRA signaling induces
neovascularization and injury repair in the infarcted myocardium.
ANP and BNP in the Failing Heart
Synthesis and secretion of ANP and BNP in the heart are
increased during hemodynamic overload and cardiac remodeling both in humans and in experimental animal models.
Cardiac remodeling is a hallmark in the progression of many
cardiovascular diseases and is characterized by LV hypertrophy and cardiac fibrosis. Accumulation of cardiac interstitial
fibrosis leads to stiffening of the LV wall, worsening of LV
systolic and diastolic function, and predisposes to cardiac
arrhythmias. Cardiac fibroblasts not only produce extracellular
matrix proteins, but also secrete a variety of growth factors
that mediate an interplay between cardiac fibroblasts and
cardiomyocytes. Several growth factors, such as Ang II, ET-1,
and platelet-derived growth factor, and various cytokines,
such as transforming growth factor-beta (TGFb) and connective tissue growth factor (CTGF), have been proposed to act in
either para- or autocrine fashion between fibroblasts and
cardiomyocytes to stimulate cardiac remodeling.37,38 Multiple
studies now indicate that NPs also directly affect the function
of cardiac fibroblasts and cardiomyocytes. Cardiovascular
effects of NPs are summarized in Figure 2.
First evidence for the role of NPs regulating fibroblast
function originate from in vitro studies. Furthermore, transgenic mouse models have been invaluable tools in investigating the roles of NPs in cardiac biology. Especially, the
experimental design utilizing mice with ANP, BNP, or NPRA
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Molecular Mechanisms of Antihypertrophic
and Antifibrotic Effects of ANP and BNP
Deletion of Ang II type 1a receptor gene (Agtr1) largely
reverses the enhanced myocardial fibrosis observed in mice
with Npr1 deficiency. In addition to Ang II, TGFb1 also appears
to play a role in antifibrotic effect of NPRA activation. ANP/
BNP signaling by NPRA, cGMP, and PKG attenuate TGFb1,
apparently in an ERK-dependent manner, and inhibit fibrotic
response induced by TGFb in cardiac fibroblasts. Specific
molecular mechanisms of antihypertrophic and -fibrotic
effects of ANP and BNP are represented in Table 2. Another
mechanism suggested for antifibrotic effect of NPs is reduced
cardiac RAA system. ANP is also linked to regulation of GATA4
activity, and a number of other signaling pathways in
cardiomyocytes have been shown to mediate the antihypertrophic effects of NPs (Table 2).
Collectively, ANP and BNP regulate a number of key
elements associated with cardiac fibrosis, such as TGFb1 and
ET-1, as well as central hypertrophy-related regulators, such
as transcription factor GATA4 and local cardiac RAA system.
Interestingly, the actions of NPs also reach to regulation of
cellular ions, mainly calcium, by numerous divergent mechanisms. In addition, NPs also regulate the activity of G-proteincoupled receptors by activation of guanylyl cyclase receptor
and formation of cGMP.
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not sufficient to block stress-induced hypertrophic
response.19 In addition to ERK, p38 MAPK has been shown
to regulate NP expression in primary cardiomyocyte culture.
Constitutive activation of p38b induces both ANP and BNP
gene expression, and inhibition of p38b by an adenovirusoverexpressing dominant-negative p38b blocks ET-1-induced
BNP transcriptional activity.20
GATA4 appears to be the key transcriptional effector
regulating transcription of ANP and BNP. GATA4 is phosphorylated at Ser105 by both ERK and p38,21–23 regulating its
DNA-binding activity and transcriptional activity.22–26 In
addition to GATA4, a number of other transcriptional regulators, such as nuclear factor of activated T-cells (NFAT), NKX2.5, Elk-1, activator protein 1, myocardin, serum response
factor, and nuclear factor kappa B, have been shown to
participate in transcriptional regulation of BNP.20,27–32 Several
studies have also indicated a central role for M-CAT element,
a thyroid-responsive element and shear stress-responsive
element on the BNP promoter regulating BNP transcriptional
activity.33–36 In conclusion, the factors regulating cardiac
hypertrophy, mainly MAPKs and GATA4 transcription factor
activity, are also associated with regulation of NP expression
levels.
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Table 1. Selected Cardiovascular Effects of ANP and BNP in In Vitro and In Vivo Animal Models
Model
Biological Effect
References
Nppa gene deletion
Genetically reduced production of ANP leads to salt-sensitive hypertension.
40
Oral administration of conjugated
BNP in dogs
BNP reduces blood pressure and increases natriuresis in normal dogs and in acute Ang II–induced
hypertension.
41
Regulation of blood pressure
Regulation of cardiac fibrosis, cardiac hypertrophy, and cardiac remodeling
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NRCF
ANP and BNP inhibit Ang II–induced proliferation of fibroblasts by inhibiting ET-1 gene expression.
42
NRCF
ANP, BNP, and CNP inhibit vasoactive peptide or growth-factor–induced proliferation of fibroblasts.
43
NRCM and NRCF
ANP inhibits NE-induced protein synthesis in cardiomyocytes and DNA synthesis in fibroblasts by
cGMP-mediated inhibition of calcium channels.
44
Nppb gene deletion
Genetically reduced production of BNP leads to development of multifocal fibrotic lesions in
subendocardial regions of ventricles in young adults and exaggerates fibrosis in response to
hemodynamic overload induced by TAC.
45,46
Nppa gene deletion9cardiac
overexpression of dnCREB
Genetically reduced production of ANP increases adverse LV remodeling and cardiac fibrosis, and
dose-dependently decreases survival in a mouse model of dilated cardiomyopathy.
47
Npr1 gene deletion
NPRA deficiency leads to modest increase in blood pressure, but results in severe cardiac
hypertrophy, fibrosis, and LV dysfunction. Normalizing the blood pressure with antihypertensive
therapy does not alleviate the adverse effects on cardiac remodeling, indicating some direct
hypertrophic mechanism mediated by deficient NPRA signaling.
48–51
Cardiac Npr1 gene deletion, or
cardiac overexpression of NPRA
Cardiac deletion of Npr1 increases cardiomyocyte size and, conversely, cardiac overexpression of
NPRA decreases cardiomyocyte cross-sectional area. Transgenic mice with cardiomyocytespecific deletion of Npr1 develop more-severe cardiac fibrosis, hypertrophy, and LV dysfunction
in response to TAC-induced pressure overload.
49,52
Npr1 gene deletion9Agtr1 gene
deletion
NPRA deficiency combined with deficient Ang II type 1a receptor gene blocks MI-induced
development of cardiac fibrosis, but not development of hypertrophy.
53
Cardiac overexpression of dnNPRA
Disruption of functional NPRA results in enhanced cardiac hypertrophy and fibrosis in response to
chronic hypertension induced by suprarenal aortic banding.
54
Regulation of cardiac function in heart failure
Subcutaneous administration of BNP
in dogs
Augmenting NPRA signaling by administration of BNP improves cardiac output while reducing
systemic vascular resistance and cardiac filling pressure in pacing-induced chronic HF.
55
Intravenous administration of
cardiotropic AAV9 carrying proBNP
in rats
Long-term cardiac proBNP delivery improves both systolic and diastolic function and reduces LV
mass in spontaneously hypertensive rats.
56
Intracardiac administration of
adenovirus carrying BNP in rats
BNP gene delivery to LV reduces cardiac fibrosis, increases capillary density, and improves LV
function in rats after experimental MI.
57
Npr1 gene deletion
Vascular regeneration in a hindlimb ischemia model is impaired in mice deficient for NPRA. NPRA
deficiency does not affect the mobilization of vascular progenitor cells from bone marrow.
58,59
Npr1 gene deletion, endothelial or
smooth muscle Npr1 gene deletion
Vascular regeneration in a hindlimb ischemia model is impaired in mice with systemic or
endothelial-cell–specific knockout of NPRA. Endothelial-cell–specific deletion of Npr1 shows
diminished angiogenesis in the heart, mild fibrosis, and diastolic dysfunction in response to TAC.
NPRA deficiency in smooth muscle cells does not affect ischemic neovascularization.
59
Overxpression of BNP
Mice overexpressing BNP shows enhanced neovascularization in response to hindlimb ischemia.
60
Regulation of angiogenesis
AAV indicates adeno-associated virus serotype 9; Agtr1, Ang II, angiotensin receptor II type 1; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; cGMP, cyclic guanosine
monophosphate; CNP, C-type natriuretic peptide; CREB, cyclic adenosine monophosphate response element-binding protein; dn, dominant negative; ET-1, endothelin 1; HF, heart failure;
LV, left ventricle; MI, myocardial infarction; NE, norepinephrine; Nppa, atrial natriuretic peptide encoding gene; Nppb, B-type natriuretic peptide encoding gene; NPRA, natriuretic peptide
receptor A; NRCF, neonatal rat cardiac fibroblasts; NRCM, neonatal rat cardiomyocytes; TAC, transverse aortic constriction.
CNP in the Diseased Heart
In the cardiovascular system, NPRB is expressed mainly in
endothelial cells and smooth muscle cells and is primarily
DOI: 10.1161/JAHA.115.002423
activated by CNP (Figure 1). Membrane preparations from
mouse hearts subjected to pressure overload show slightly
higher guanylyl cyclase activity in response to saturating
concentrations of ANP than upon stimulation by CNP.76
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Table 2. Selected Molecular Mechanisms of Antihypertrophic and Antifibrotic Effects of ANP and BNP
Model
Biological Effect
References
Human CF
BNP inhibits TGFb1-induced fibroblast proliferation and expression of fibrotic marker genes collagen
1, fibronectin, CTGF, PAI-1, and TIMP3. BNP treatment induces activation of ERK whereas chemical
inhibition of ERK blocks the antifibrotic effects of BNP.
61
Mouse CF
ANP/cGMP-mediated PKG induces phosphorylation of Ser309 and Thr388 residues of Smad3, which
disrupts TGFb1-induced nuclear translocation of pSmad3 (phosphorylated at Ser423/425) and
attenuates the profibrotic effects of TGFb1.
62
NRCM and NRCF co-culture
ANP/BNP reduce aldosterone synthase mRNA expression in cardiac cells, which subsequently
suppresses local cardiac RAA system.
63
Cardiac Npr1 gene deletion, MR
antagonist treatment
Mice with cardiomyocyte-restricted knockdown of either NPRA or its downstream effector, PKG,
develop enhanced LV hypertrophy, fibrosis, and dysfunction in response to TAC. Treating these mice
with MR antagonist eplerenone, LV hypertrophy, fibrosis, dilatation, and dysfunction are attenuated.
ANP signaling, mediated by NPRA and formation of cGMP, inhibits nuclear translocation of MR and
thus its transcriptional activity.
64
Microarray from Npr1 gene
deleted mice
Microarray analysis of NPRA knockout LV tissue shows involvement of many factors, including
calmodulin-CaMK-HDAC-Mef2 and PKC-MAPK-GATA4, in development of cardiac hypertrophy and
fibrosis.
65
NRCF
ANP suppresses the expression of profibrotic ET-1 and inhibits GATA4 binding activity to ET-1
promoter. In addition, ET-1-induced GATA4 binding activity and GATA4 phosphorylation at Ser105,
involved in stress-induced LV hypertrophy, are also partially inhibited by cotreatment of cells with
ANP.
66
Npr1 gene deletion
NPRA-deficient mice have enhanced calcineurin protein phosphatase activity, increased nuclear
translocation of NFATc4, and increased GATA4 DNA-binding activity. Pharmacological inhibition of
calcineurin suppresses both calcineurin activation and attenuates the development of cardiac
hypertrophy.
67
Regulation of TGFb signaling
Regulation of cardiac RAA system
Regulation of transcription factor GATA4
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Regulation of intracellular ion homeostasis and pH
Npr1 gene deletion
NPRA-deficient mice have enhanced activity of NHE-1, one of the main factors governing physiological
intracellular pH in the heart. The increased activity of NHE-1 increases cellular sodium load and
subsequently intracellular calcium concentration through NCX-1. Inhibition of NHE-1 by cariporide
inhibits both development of cardiac hypertrophy and fibrosis. NHE-1 induction is associated with
activation of CaMKII and Akt whereas adverse outcome in NPRA-deficient mice attributed to
enhanced activity of MEK1-ERK1/2 and NFAT are not associated with NHE-1.
68
Isolated hearts from Npr1
gene-deleted mice
Hearts of NPRA-deficient mice have increased expression and autophosphorylation of CaMKII, and
inhibition of CaMKII inhibits development of LV hypertrophy and fibrosis.
69
NRCM, Npr1 gene
deletion9cardiac
overexpression of TRPC6
ANP induces phosphorylation of TRPC6 at PKG phosphorylation site, inhibits calcium flux, and
calcineurin-NFAT-dependent hypertrophy. Overexpression of TRPC6 in mice lacking NPRA
exacerbates cardiac hypertrophy.
70
Regulation of cell survival kinases and regulators of GPCR signaling
Cardiac Npr1 gene
deletion9eNOS gene deletion
NPRA deficiency in cardiomyocytes of hypertensive eNOS knockout mice leads to cardiac hypertrophy
and increased fibrosis, which is accompanied by marked activation of both ERK1/2 and calcineurin.
71
Overexpression of BNP
Genetic overexpression of BNP reduces Ang II–induced ERK activation in LV.
72
Fetal rat astrocytes, NRCM,
Npr1 gene deletion9cardiac
overexpression of RGS4
ANP stimulates phosphorylation of RGS4 and association of RGS4 with Gaq in vitro, whereas
phosphorylation of RGS4 is reduced in hearts of NPRA knockout mice. RGS4 is required for the
antihypertrophic effect of ANP in vitro; cardiomyocyte-specific overexpression of RGS4 suppresses
calcineurin activity and cardiac hypertrophy in NPRA-deficient mice.
73,74
NRCM, subcutaneous
administration of ANP in mice
ANP induces nuclear accumulation of zyxin and activated Akt, antagonizing apoptosis in
cardiomyocytes in vitro and in vivo.
75
Ang II indicates angiotensin II; ANP, atrial natriuretic peptide; BNP, B-type natriuretic peptide; CaMKII, Ca2+/calmodulin-dependent kinase II; CF, cardiac fibroblast; cGMP, cyclic guanosine
monophosphate; CTGF, connective tissue growth factor; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinase; ET-1, endothelin 1; GPCR, G-protein-coupled
receptor; Gaq, guanine nucleotide-binding protein (G protein) aq subunit; HDAC, histone deacetylase; LV, left ventricle; MAPK, mitogen-activated protein kinase; MR, mineralocorticoid
receptor; NCX-1, sodium-calcium exchanger 1; NFAT, nuclear factor of activated T-cells cytoplasmic 4 isoform; NHE-1, sodium hydrogen antiporter 1; NPRA, natriuretic peptide receptor A;
NRCF, neonatal rat cardiac fibroblast; NRCM, neonatal rat cardiomyocyte; PAI-1, plasminogen activator inhibitor 1; PKC, protein kinase C; PKG, protein kinase G; RAA, renin-angiotensinaldosterone system; RGS4, regulator of G protein signaling subtype 4; Ser, serine; TAC, transverse aortic constriction; TGFb1, transforming growth factor beta 1; Thr, threonine; TIMP3,
tissue inhibitor of metalloproteinase 3; TRPC6, transient receptor potential canonical channel 6.
DOI: 10.1161/JAHA.115.002423
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Natriuretic Peptides in the Regulation of
Energy Metabolism, Development of
Metabolic Syndrome, and Diabetes
The energy needed to maintain cardiac contractility is mainly
produced by fatty acid oxidation in mitochondria, the
organelles that are highly abundant in heart tissue. However,
if needed or when available, the heart is able to use other
energy substrates, such as carbohydrates, lipids, amino acids,
and ketone bodies, for adenosine triphosphate (ATP) production.91 In pathological hypertrophy, cardiac metabolism is
characterized by reduced fatty acid oxidation and increased
glucose uptake and glycolysis. On the other hand, in diabetes,
insulin resistance limits glucose entry into cardiomyocytes to
be metabolized for energy. In diabetes, fatty acid oxidation is
increased and associated with accumulation of lipids and
increased consumption of oxygen. These metabolic derangements lead to impaired cardiac function. However, the
situation is quite complex—no matter how beneficial
enhanced glucose use is in cardiac events, promotion of fatty
acid oxidation would be rather desirable for long-term source
of energy production.
In addition to their chief function as cardiovascular
hormones, NPs have been shown to contribute to regulation
of energy metabolism. ANP and BNP serve as potent
mediators of lipolysis in adipocytes, whereas CNP has only
a minor lipolytic effect.92 Insulin is known to counteract the
lipolytic effect induced by catecholamines in sympathetic
activity by counteracting the cyclic adenosine monophosphate (cAMP)/protein kinase A–signaling pathway. However, insulin has no effect on ANP-induced lipolysis in
adipocytes. Lipolysis induced by NPs is likely to occur by a
cGMP-dependent mechanism and to be independent of the
activation of sympathetic nervous system and cAMP signaling.93 When infused into the circulation or administered into
subcutaneous adipose tissue in humans, ANP leads to lipid
mobilization. Whereas endurance training improves lipid
mobilization, regulated by catecholamines and insulin, exercise also induces release of NPs from the heart, which
contribute to lipid mobilization concomitantly with sympathetic activation. NPs have also been shown to increase
mitochondrial oxidative metabolism and lipid oxidation in
skeletal muscle, leading to enhanced energy metabolism in
muscle.94
Opposite to white adipose tissue as a fat storage, brown
adipose tissue is thermogenic by producing heat while
dissipating energy. The physiological importance of brown
adipose tissue in the regulation of energy metabolism in
adults has recently emerged (reviewed in previous work95).
Interestingly, NPs may regulate brown adipose tissue and
activate its thermogenic activity while controlling the status of
white adipose tissue. NPs can promote “browning” of white
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However, in preparations from failing mouse heart, the
response elicited by CNP is 2-fold compared to the response
of ANP, thus suggesting marked reduction in NPRA activity,
but no change in NPRB activity.76 CNP levels are substantially
increased in myocardial tissue in patients with HF.77 However,
plasma levels of CNP are very low even in patients with severe
HF. Levels of circulating CNP actually appear to decrease in
rats during aging, and this correlates with an increase in
cardiac fibrosis.78 In addition to the heart, head and neck
tissue are important sources of CNP.79
In vivo cleavage of proCNP by furin yields 50 amino acid
amino terminal proCNP (NT-proCNP) and CNP1-53, which is
the precursor for the biologically active mature form of CNP
(CNP1-22). Administration of CNP in vitro has been shown to
exert antihypertrophic effects on cardiomyocytes as well as
antiproliferative effects on rat vascular smooth muscle cells
and primary fibroblasts.80 Of the three NPs, CNP has been
shown to be most potent at inhibiting growth-factor–induced
smooth muscle cell migration.81 CNP has only minimal renal
actions, but it has been shown to induce vasorelaxation and,
interestingly, CNP infusion to dogs has been shown to lower
blood pressure more effectively than ANP without natriuretic
effect.82 Plasma levels of CNP1-53 are also elevated in
patients with acute decompensated HF,83 and recent data
suggest that in addition to CNP1-22, the CNP1-53 peptide
also has biological actions in in vitro and in vivo models.84
Apart from regulating cardiovascular functions, disruption of
CNP gene in mice results in impaired longitudinal growth of
long bones and dwarfism.85 Mutations in the NPRB gene
(NPR2) in humans impairs skeletal growth, and mice with
targeted deletion of Npr2 show impaired endochondral
ossification, defective development of female reproductive
organs, and early mortality.86
Blood pressure analysis of mice with Npr2 deletion revealed
no difference compared to wild-type littermates. Fibroblasts
from NPRB-deficient mice, however, showed blunted cGMP
elevation in response to CNP stimulation.86 Overexpression of
dominant-negative NPRB in rats led to progressive cardiac
hypertrophy that was not owing to elevation in blood
pressure.87 On the other hand, continuous infusion of CNP
for 2 weeks in rats with experimental MI significantly reduced
both cardiac hypertrophy and fibrosis.88 Furthermore, transgenic overexpression of CNP in cardiomyocytes has been
shown to prevent development of LV hypertrophy post-MI.89
The cGMP-dependent signaling appears to be central for
antifibrotic effects of CNP.88,90 Evidence from Burnett’s
laboratory suggests that a non-cGMP-dependent pathway also
mediates the antifibrotic effects of CNP.78 In conclusion,
antifibrotic and -hypertrophic effects of CNP appear to be
mediated both by activation of NPRB and by a noncGMP-dependent mechanism, whereas blood-pressure–
lowering effect of CNP is not dependent on activation of NPRB.
Myocardial Effects of Natriuretic Peptides
Kerkel€a et al
DOI: 10.1161/JAHA.115.002423
of their contribution and necessity to metabolic events
remains to be elucidated.
In summary, aside from their classic hemodynamic effects,
NPs have been associated with regulation of numerous
physiological functions controlling energy metabolism, as
summarized in Figure 2. NPs may activate lipolysis, lipid
oxidation, and mitochondrial respiration and promote white
adipose tissue browning, increase muscular oxidative capacity, and protect against diet-induced obesity and insulin
resistance. These metabolic events are, in turn, closely
associated with development of cardiovascular diseases. By
secretion of NPs, the heart may thus play a central role in
regulation of energy balance.
Novel Therapeutic Approaches
Recombinant ANP (carperitide) was first approved for treatment of patients with acute decompensated congestive HF in
Japan in 1995. Recombinant BNP (nesiritide) has been
approved by the U.S. Food and Drug Administration (FDA)
for the same indication in 2001. However, data from the
Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND-HF) showed a lack of
efficacy on rehospitalization for HF or death from any cause—
the major clinical endpoints.107 In a pilot study conducted
with 40 patients with New York Heart Association functional
class II to III HF, indicating slight to marked limitation in
activity owing to cardiovascular symptoms, chronic protein
therapy with subcutaneous BNP was sufficient to improve
Minnesota Living with Heart Failure score, LV remodeling, and
LV filling pressure.108
Novel therapeutic approaches include oral delivery of
conjugated BNP, which activated cGMP and reduced mean
arterial pressure in a model of acute Ang II–induced
hypertension.41 More recently, cenderitide, a chimeric
peptide that simultaneously activates NPRA and NPRB,
has entered clinical trials for preservation of LV function
post-MI. Cenderitide has also been shown to be more
resistant to degradation by neutral endopeptidase neprilysin
compared to ANP, BNP, and CNP.109 ProBNP has been
shown to have 7 O-glycosylation sites in the NT-proBNP
region and furin is effective in cleaving deglycosylated, but
not intact proBNP.110,111 A subsequent study showed that
O-glycosylation of T71 residue in proBNP attenuates its
processing into active BNP.112 Nonglycosylated proBNP is
processed into active BNP1-32 in plasma, but the processing is delayed in plasma samples from patients with HF.113
When compared to healthy controls, the processed BNP is
degraded more rapidly in HF with preserved ejection
fraction whereas the processing is delayed in HF with
reduced ejection fraction.113 Characterization of the regulatory mechanisms of NP processing and degradation is
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adipocytes by upregulating mitochondrial uncoupling receptor
1 and peroxisome proliferator-activated receptor (PPAR)-c
coactivator (PGC)-1a, leading to increased mitochondrial
biogenesis and uncoupled respiration similarly in response
to b-adrenergic sympathetic activity, in a p38 MAPKdependent manner.96
In addition to increased insulin sensitivity, achieved by
alterations in adipose tissue and energy expenditure of
skeletal muscle, NPs may also increase insulin secretion.
When studied in a mouse model, ANP was found to block
ATP-dependent potassium channel activity in pancreatic
b-cells, to increase glucose-elicited calcium signaling and
enhance glucose-stimulated insulin secretion in islets of
Langerhans.97 It should be noted, however, that long-term
exposure to ANP may inhibit glucose-stimulated insulin
secretion from isolated islets, which is accompanied with
reduced ATP generation in b-cells in response to glucose.98
To pinpoint the importance of natriuretic peptides as
metabolic regulators, BNP-overexpressing mice which were
fed on high-fat diet were protected against diet-induced
obesity and insulin resistance.99 This was associated with
increased muscle mitochondrial biogenesis and fat oxidation
through upregulation of PPAR-c coactivator PGC-1a and
PPAR-d. Furthermore, chronic BNP treatment at low dose
reduced plasma glucose levels, improved metabolic profile,
and prevented development of myocardial dysfunction in
obese diabetic mice.100 When BNP levels were determined
from HF patients, obese patients indeed had reduced BNP
plasma levels, although no difference in severity of HF or
proinflammatory cytokine levels were detected.101
In humans, metabolic risk factors and components of
metabolic syndrome were found to be associated with low
natriuretic peptide levels in plasma.102 In a prospective study,
low plasma levels of ANP were found to predict development
of future diabetes, suggesting a causal role of ANP deficiency
in diabetes development.103 In another study, higher NP levels
were associated with a favorable body-fat profile, including
lower visceral fat and reduced insulin resistance.104 In a
follow-up study, higher NP levels were associated with
reduced risk for diabetes.105
NPs can also modulate secretion of adipokines, such as
adiponectin and leptin, from adipose tissue and secretion of
cytokines from adipose tissue macrophages, as studied
in vitro. NPs may thus participate in regulating inflammatory
status in obesity. Some of the favorable metabolic effects of
NPs may even be mediated by their anti-inflammatory and
hepatoprotective effects in liver.93 CNP, mainly expressed in
the brain, might participate in regulation of energy metabolism by controlling food intake and satiety. Various actions of
NPs in energy metabolism have been recently comprehensively reviewed.106 Although there are extensive data showing
NPs to play a role in controlling energy metabolism, the extent
Myocardial Effects of Natriuretic Peptides
Kerkel€a et al
DOI: 10.1161/JAHA.115.002423
b-amyloid, of which aggregation into plaques is one of the
hallmarks of AD.120 It is not likely that peripheral inhibition of
neprilysin affected brain b-amyloid levels by inhibiting the
peripheral sink effect, which is suggested as an alternative for
b-amyloid removal.121,122 However, if LCZ696 was to penetrate the blood–brain barrier, it could, in theory, accelerate the
progression of AD by reducing b-amyloid degradation in brain.
On the other hand, vascular diseases, such as hypertension,
are known risk factors for the progression of AD, and an ARB
component of LCZ696 could therefore attenuate the progression of AD. Notably, dementia-related adverse effects were
not increased in the Paradigm-HF trial. The trial, however, was
not designed for evaluation of the cognitive function, and
follow-up studies are needed to address possible adverse
effects on cognitive function.
Another novel drug in the group of NP-modifying molecules
is ularitide, which is the chemically synthesized form of the
human NP, urodilatin. Urodilatin is produced in humans by
alternative processing of proANP in distal renal tubule cells
and it participates in sodium homeostasis. Ularitide causes
vasodilation, diuresis, and natriuresis by binding to NPRA and
activation of the cGMP pathway. Ularitide is currently in a
phase III clinical study, called TRUE-AHF, to study its efficacy
and safety in treatment of HF.123 Ularitide actually shares
many pharmacological properties with the recombinant BNPanalog, nesiritide.
Perspectives
NPs function to maintain normal salt and water balance and
play a critical role in regulating arterial blood pressure
through their natriuretic, diuretic, and vasodilator effects.
ANP and BNP are well-established markers of both acute
and chronic HF, and the circulating levels of NPs have been
shown to correspond to the degree of LV dysfunction.124 In
addition, NPs provide long-term prognostic value in HF
patients and in those with acute cardiac ischemia.125,126
There is also evidence that levels of circulating NP provide
predictive value in the healthy population.127 There is now
compelling evidence showing that NPs are also important
regulators of cardiac structure and function. Especially, it
appears that NPs are key physiological antagonists of the
cardiac RAA system. These findings may provide novel
indications for therapy with NPs and their conjugates. In
addition, the favorable effects of NPs on cardiac structure
should be considered in the design of novel HF therapies.
Countering the detrimental changes in expression of genes
regulating cardiac hypertrophy, fibrosis, and calcium handling is central in preventing adverse structural and
functional myocardial remodeling. Therefore, it may be a
desirable goal for HF therapy to preserve the elevated levels
of natriuretic peptides.
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thus crucial and may offer novel therapeutic options for
treatment of HF.
Neutral endopeptidase neprilysin is a membrane-bound
endopeptidase that is widely expressed in mammals, including
the kidney, lung, endothelial cells, vascular smooth muscle
cells, cardiomyocytes, fibroblasts, adipocytes, and the brain.8
Neprilysin has been shown to degrade several vasoactive
peptides, including natriuretic peptides, bradykinin, and
adrenomedullin. Candoxatril is a neprilysin inhibitor developed
for clinical use. In patients with HF, candoxatril increased ANP
and BNP levels, but had unfavorable vascular and cardiac
effects.114 Combining neprilysin inhibition with inhibition of
angiotensin-converting enzyme (ACE) showed beneficial
effects in experimental models. However, clinical trials with
omapatrilat, which inhibits both neprilysin and ACE, proved
unsuccessful owing to serious angioedema.115 A plausible
explanation for the increased incidence of angioedema is
inhibition of breakdown of bradykinin and aminopeptidase P
by omapatrilat.
Angiotensin receptor blockers (ARBs) have a lower risk of
angioedema compared to ACE inhibitors, and combining
neprilysin inhibition with angiotensin receptor blockade was
shown to have an additive blood-pressure–lowering effect
compared to valsartan alone without the increased incidence
of angioedema.116 The Paradigm-HF study was conducted to
compare the efficacy of combined angiotensin receptor
blockade and neprilysin inhibition by valsartan/sacubitril
(previously known as LCZ696) to that of enalapril in patients
with chronic HF and reduced ejection fraction. The trial was
stopped early because of the overwhelming benefit of
LCZ696. Combined angiotensin receptor blockade and
neprilysin inhibition by LCZ696 significantly reduced the
risk of hospitalization for HF and the number of deaths for
cardiovascular causes.117 Importantly, no major safety
concerns of the combination emerged during the study. It
should be noted, however, that the LCZ696 group developed
significantly more cases of hypotension, which was already
applied as exclusion criteria. This raises a concern of
hypotension as a potential adverse effect with not just
LCZ696, but possibly also with other NP-enhancing drugs.
Simultaneous blockade of angiotensin receptors and neprilysin by LCZ696 has also shown efficacy in an experimental
model attenuating cardiac remodeling and dysfunction in
rats post-MI.118 The FDA has approved this drug, valsartan/
sacubitril, as a treatment for HF in July 2015.
Given that higher NP levels have been shown to associate
with a favorable body-fat profile and with reduced risk for
diabetes, it will be of interest to assess whether neprilysin
inhibition is also sufficient to affect energy metabolism. Some
concerns have been raised over possible risk for Alzheimer’s
disease (AD) resulting from neprilysin inhibition.119 The brain
neprilysin has been shown to play a key role in degrading
Myocardial Effects of Natriuretic Peptides
Kerkel€a et al
This work was supported by the Academy of Finland, the
Finnish Foundation for Cardiovascular Research, and the
Sigrid Juselius Foundation.
Disclosures
None.
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Key Words: cardiac hypertrophy • fibrosis • heart failure •
metabolism • natriuretic peptides
DOI: 10.1161/JAHA.115.002423
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Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events
Risto Kerkelä, Johanna Ulvila and Johanna Magga
J Am Heart Assoc. 2015;4:e002423; originally published October 27, 2015;
doi: 10.1161/JAHA.115.002423
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